There is a suite of emerging viruses that are endemic, pandemic, engineered, or weaponized. To date, there is no broad-spectrum antiviral therapy that can effectively prevent infection or treat illness resulting from these viruses. According to the U.S. Centers for Disease Control and Prevention (CDC; Rotz et al, CDC Emerging Infectious Diseases Vol. 8, No. 2, 2002) there are six Category A threats, which includes smallpox, which is caused by, e.g., variola virus (Smallpox), and viral hemorrhagic fever, which is caused by, e.g., filoviruses, such as Ebola virus, bunyaviruses, such as hantavirus, and arenaviruses, such as Lassa virus. Category A agents have the greatest potential for adverse public health impact with mass casualties. Biological agents that have potential for large-scale dissemination with resultant illness but generally fewer fatalities are classified as Category B threats. Several viral threats are identified as Category B threats; these include viral encephalitis, such as, e.g., Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), which are all alphaviruses. There are also many emerging Category C threats, which include diseases caused by Nipah virus and hantavirus.
In addition to the CDC list, the U.S. Department of Health and Human Services (HHS) has released a list of viruses under their Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) program that lists Arenaviridae (e.g., Junin and Lassa viruses), Filoviridae (e.g., Ebola and Marburg viruses), Poxyiridae (Smallpox and monkey pox viruses), and Orthomyxoviridae (e.g., Influenzavirus A, such as H5N1 and H1N1 viruses). Clearly it is not feasible to vaccinate an entire population against all viral strains of all of these viral agents. Indeed, the large-scale vaccination of the public against bioterrorist threats, e.g., anthrax, was a failure.
Interferon-alpha (IFN-α) has been used clinically and commercially (e.g., RoferonA®, IntronA®, Pegasys®, PegIntron® etc) to successfully treat various cancers, including, e.g., malignant melanoma, hairy cell leukemia, non-Hodgkin's lymphoma, AIDS-related Kaposi's sarcoma, as well as infectious diseases, such as severe acute respiratory syndrome (SARS), chronic Hepatitis B, and chronic Hepatitis C. IFN-α is a type I interferon, which binds to the IFN-α receptor.
IFN-α is one of the earliest cytokines released by antigen presenting cells as part of the innate immune response. It is directly responsible for NK and T cell responsiveness, which drives the subsequent immune response. Because of the early response of IFN-α in the immune cascade, its primary role is suggested to be to induce a priming state during the initial response to infection, and it has been shown that low dose IFN-α results in increased protection from a viral challenge.
IFN-α, as a recombinant human therapeutic agent, is expensive to manufacture by cGMP, is hindered by its short half-life in vivo, and is produced in a non-glycosylated form. IFN-α has an initial distributive half-life of 7 minutes and a beta half-life of 2 to 5 hours. This rapid decay requires multiple injections, usually three times weekly, to maintain therapeutic levels. Thus, at $2,500 per dose retail, the cost of using recombinant human IFN-α as a broad-spectrum antiviral in counter bioterrorism or military operations is prohibitive.
In order to mitigate this rapid in vivo degradation, PEGylated forms of IFN-α have been developed that have half-lives that are on the order of days instead of hours, thus reducing the number of injections to once per week. Nonetheless, the PEGylation process has been shown to reduce the activity of the IFN-α, and PEG-IFN-α is even more expensive to manufacture than IFN-α.
Currently, there is a need for a broad-spectrum antiviral that could be administered for pre- or post-exposure prophylaxis to guard against or in response to, respectively, infectious diseases, such as viral threats (e.g., a viral bioweapon used during a terrorist event or in the event of pandemic disease).